Project Summary Our sense of vision begins when single rod and cone photoreceptors absorb light and produce an electrical signal, which higher centers in the brain then analyze to alter our behavior. We learn even as children that rods are the photoreceptors we use to see dim light and cones to see bright light and color. This view is supported by behavioral measurements and electrical recording, which all seem to show that rods are primarily used to detect dim light and become essentially non-functional as the ambient illumination increases during daylight. Recent experiments have however challenged this notion and demonstrated that rods can continue to respond even in light so strong that a large fraction of the rod photopigment is bleached. These observations challenge our understanding of rod function in bright light. The purpose of this study is to thoroughly reexamine rod current and voltage responses to persistent bright illumination over extended durations of time. Our preliminary evidence shows surprisingly that the responsiveness of rods can recover over the course of hours during persistent bright illumination. Here we are seeking to investigate the molecular and mechanistic basis of this rod recovery and its dependence on time and light intensity in mice. In particular, we will leverage several lines of transgenic mice having targeted mutations in components of the phototransduction cascade. We also are interested in how photoresponse recovery in rods can be made faster and more robust, as observed in cones. We we will explore these phenomena by genetically transferring certain molecular features of cone phototransduction into the rods by leveraging mice with targeted mutations to reduce the sensitivity of rods and increase the rate of photoresponse and photopigment decay. We hope to show which factors are responsible for the differential responsiveness of the two photoreceptors in bright light. These phenomena are not only important to our understanding of the physiology of photoreceptors, they are also essential for photoreceptor survival because rods die when outer- segment channels remain closed for too long a time. In addition, understanding how to make rod photoreceptors more like cones may have therapeutic value, as deficiencies in cone vision may be mitigated by shifting the responsiveness of rods to brighter background light intensities. Because of the importance of these phenomena to photoreceptor function in health and disease, the Retinal Disease Program of the NEI has as one of its program objectives to ?analyze the mechanisms underlying light adaptation and recovery following phototransduction?.